The laboratory of John D. Fryer, Ph.D., studies the pathogenesis of Alzheimer's disease, focusing on molecular mechanisms of known genetic risk factors. Some of these genetic risk factors are known to be involved in immune system function, likely mediated by the resident immune cells of the brain (microglia).

Interestingly, the same populations at risk of Alzheimer's disease are also at high risk of sepsis, a devastating condition that can lead to disability and long-term cognitive dysfunction. Dr. Fryer seeks to understand whether these inflammatory pathways converge on individuals to initiate a spiraling cognitive decline.

His research team pursues these research avenues with biochemical and molecular techniques, using a variety of mouse genetic models and in vitro systems.

Focus areas

• The role of CLU and TREM2 in Alzheimer's disease pathogenesis. The CLU and TREM2 genes are important genetic risk factors for the development of Alzheimer's disease. Dr. Fryer's lab uses mouse models of Alzheimer's disease to determine how these genes are involved in the development of amyloid formation in brain parenchyma as well as cerebral amyloid angiopathy. The lab also studies the role of these genes in the formation of tau pathology.
• Consequences of neuroinflammation following sepsis. Older adults who survive sepsis are at high risk of developing long-term cognitive impairment. Dr. Fryer's team seeks to understand whether specific molecules play a prominent role in this process, and could therefore be targeted for therapy to prevent post-sepsis cognitive decline.
• The role of the gut microbiome in mental health. The microbes in the gut and their collective genomes (the microbiome) have an increasingly recognized role in human health and disease. Dr. Fryer's team found that a high-fat diet and exercise both dramatically alter the levels of these microbes, with some specifically associationed with levels of anxiety and cognition. The lab is now pursuing investigations of how the gut microbiome can be manipulated to alter mood and cognition in both mouse models and human populations.

Significance to patient care

All diseases have profound impacts on individuals and society, but brain diseases are particularly devastating because they often rob individuals of their very identities. Dr. Fryer's hope is that a greater understanding of some of the basic molecular mechanisms underlying these diseases will lead to new therapies.